The treatment modalities for inflammatory bowel disease (IBD) have been rapidly expanding over the past years. Biological therapies are the leading choice of therapy in moderate and severe IBD, aiming to help patients achieve meaningful clinical, endoscopic, and laboratory responses. However, some patients are primary nonresponders and fail to show any response, while others relapse after an initial response, also known as secondary nonresponders. In this article, we review the mechanism of action of the currently available biological therapies for IBD, assessment of treatment response, the nonresponse rates to each therapy, clinical and laboratory factors affecting the efficacy of therapies, and suggested targeted drug levels.